TY - JOUR
T1 - IFNγ-Dependent Tissue-Immune Homeostasis Is Co-opted in the Tumor Microenvironment
AU - Nirschl, Christopher J.
AU - Suárez-Fariñas, Mayte
AU - Izar, Benjamin
AU - Prakadan, Sanjay
AU - Dannenfelser, Ruth
AU - Tirosh, Itay
AU - Liu, Yong
AU - Zhu, Qian
AU - Devi, K. Sanjana P.
AU - Carroll, Shaina L.
AU - Chau, David
AU - Rezaee, Melika
AU - Kim, Tae Gyun
AU - Huang, Ruiqi
AU - Fuentes-Duculan, Judilyn
AU - Song-Zhao, George X.
AU - Gulati, Nicholas
AU - Lowes, Michelle A.
AU - King, Sandra L.
AU - Quintana, Francisco J.
AU - Lee, Young suk
AU - Krueger, James G.
AU - Sarin, Kavita Y.
AU - Yoon, Charles H.
AU - Garraway, Levi
AU - Regev, Aviv
AU - Shalek, Alex K.
AU - Troyanskaya, Olga G.
AU - Anandasabapathy, Niroshana
N1 - Publisher Copyright:
© 2017 Elsevier Inc.
PY - 2017/6/29
Y1 - 2017/6/29
N2 - Homeostatic programs balance immune protection and self-tolerance. Such mechanisms likely impact autoimmunity and tumor formation, respectively. How homeostasis is maintained and impacts tumor surveillance is unknown. Here, we find that different immune mononuclear phagocytes share a conserved steady-state program during differentiation and entry into healthy tissue. IFNγ is necessary and sufficient to induce this program, revealing a key instructive role. Remarkably, homeostatic and IFNγ-dependent programs enrich across primary human tumors, including melanoma, and stratify survival. Single-cell RNA sequencing (RNA-seq) reveals enrichment of homeostatic modules in monocytes and DCs from human metastatic melanoma. Suppressor-of-cytokine-2 (SOCS2) protein, a conserved program transcript, is expressed by mononuclear phagocytes infiltrating primary melanoma and is induced by IFNγ. SOCS2 limits adaptive anti-tumoral immunity and DC-based priming of T cells in vivo, indicating a critical regulatory role. These findings link immune homeostasis to key determinants of anti-tumoral immunity and escape, revealing co-opting of tissue-specific immune development in the tumor microenvironment.
AB - Homeostatic programs balance immune protection and self-tolerance. Such mechanisms likely impact autoimmunity and tumor formation, respectively. How homeostasis is maintained and impacts tumor surveillance is unknown. Here, we find that different immune mononuclear phagocytes share a conserved steady-state program during differentiation and entry into healthy tissue. IFNγ is necessary and sufficient to induce this program, revealing a key instructive role. Remarkably, homeostatic and IFNγ-dependent programs enrich across primary human tumors, including melanoma, and stratify survival. Single-cell RNA sequencing (RNA-seq) reveals enrichment of homeostatic modules in monocytes and DCs from human metastatic melanoma. Suppressor-of-cytokine-2 (SOCS2) protein, a conserved program transcript, is expressed by mononuclear phagocytes infiltrating primary melanoma and is induced by IFNγ. SOCS2 limits adaptive anti-tumoral immunity and DC-based priming of T cells in vivo, indicating a critical regulatory role. These findings link immune homeostasis to key determinants of anti-tumoral immunity and escape, revealing co-opting of tissue-specific immune development in the tumor microenvironment.
KW - IFNγ
KW - dendritic cells
KW - differentiation
KW - homeostasis
KW - immunotherapy
KW - melanoma
KW - suppressor-of-cytokine-signaling 2 (SOCS2)
KW - tissue mononuclear phagocytes
KW - tolerance
KW - tumor microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85021662906&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85021662906&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2017.06.016
DO - 10.1016/j.cell.2017.06.016
M3 - Article
C2 - 28666115
AN - SCOPUS:85021662906
SN - 0092-8674
VL - 170
SP - 127-141.e15
JO - Cell
JF - Cell
IS - 1
ER -